Extracellular Kir2.1C122Y Mutant Upsets Kir2.1-PIP2 Bonds and Is Arrhythmogenic in Andersen-Tawil Syndrome.

BACKGROUND: Andersen-Tawil syndrome type 1 is a rare heritable disease caused by mutations in the gene coding the strong inwardly rectifying K+ channel Kir2.1. The extracellular Cys (cysteine)122-to-Cys154 disulfide bond in the channel structure is crucial for proper folding but has not been associated with correct channel function at the membrane. We evaluated whether a human mutation at the Cys122-to-Cys154 disulfide bridge leads to Kir2.1 channel dysfunction and arrhythmias by reorganizing the overall Kir2.1 channel structure and destabilizing its open state. METHODS: We identified a Kir2.1 loss-of-function mutation (c.366 A>T; p.Cys122Tyr) in an ATS1 family. To investigate its pathophysiological implications, we generated an AAV9-mediated cardiac-specific mouse model expressing the Kir2.1C122Y variant. We employed a multidisciplinary approach, integrating patch clamping and intracardiac stimulation, molecular biology techniques, molecular dynamics, and bioluminescence resonance energy transfer experiments. RESULTS: Kir2.1C122Y mice recapitulated the ECG features of ATS1 independently of sex, including corrected QT prolongation, conduction defects, and increased arrhythmia susceptibility. Isolated Kir2.1C122Y cardiomyocytes showed significantly reduced inwardly rectifier K+ (IK1) and inward Na+ (INa) current densities independently of normal trafficking. Molecular dynamics predicted that the C122Y mutation provoked a conformational change over the 2000-ns simulation, characterized by a greater loss of hydrogen bonds between Kir2.1 and phosphatidylinositol 4,5-bisphosphate than wild type (WT). Therefore, the phosphatidylinositol 4,5-bisphosphate-binding pocket was destabilized, resulting in a lower conductance state compared with WT. Accordingly, on inside-out patch clamping, the C122Y mutation significantly blunted Kir2.1 sensitivity to increasing phosphatidylinositol 4,5-bisphosphate concentrations. In addition, the Kir2.1C122Y mutation resulted in channelosome degradation, demonstrating temporal instability of both Kir2.1 and NaV1.5 proteins. CONCLUSIONS: The extracellular Cys122-to-Cys154 disulfide bond in the tridimensional Kir2.1 channel structure is essential for the channel function. We demonstrate that breaking disulfide bonds in the extracellular domain disrupts phosphatidylinositol 4,5-bisphosphate-dependent regulation, leading to channel dysfunction and defects in Kir2.1 energetic stability. The mutation also alters functional expression of the NaV1.5 channel and ultimately leads to conduction disturbances and life-threatening arrhythmia characteristic of Andersen-Tawil syndrome type 1.

Nuclear receptor 5A2 regulation of Agrp underlies olanzapine-induced hyperphagia.

Antipsychotic (AP) drugs are efficacious treatments for various psychiatric disorders, but excessive weight gain and subsequent development of metabolic disease remain serious side effects of their use. Increased food intake leads to AP-induced weight gain, but the underlying molecular mechanisms remain unknown. In previous studies, we identified the neuropeptide Agrp and the transcription factor nuclear receptor subfamily 5 group A member 2 (Nr5a2) as significantly upregulated genes in the hypothalamus following AP-induced hyperphagia. While Agrp is expressed specifically in the arcuate nucleus of the hypothalamus and plays a critical role in appetite stimulation, Nr5a2 is expressed in both the CNS and periphery, but its role in food intake behaviors remains unknown. In this study, we investigated the role of hypothalamic Nr5a2 in AP-induced hyperphagia and weight gain. In hypothalamic cell lines, olanzapine treatment resulted in a dose-dependent increase in gene expression of Nr5a2 and Agrp. In mice, the pharmacological inhibition of NR5A2 decreased olanzapine-induced hyperphagia and weight gain, while the knockdown of Nr5a2 in the arcuate nucleus partially reversed olanzapine-induced hyperphagia. Chromatin-immunoprecipitation studies showed for the first time that NR5A2 directly binds to the Agrp promoter region. Lastly, the analysis of single-cell RNA seq data confirms that Nr5a2 and Agrp are co-expressed in a subset of neurons in the arcuate nucleus. In summary, we identify Nr5a2 as a key mechanistic driver of AP-induced food intake. These findings can inform future clinical development of APs that do not activate hyperphagia and weight gain.

Understanding the Electronic Effects of Lewis Acid Catalysts in Accelerating Polar Diels-Alder Reactions.

The electronic effects of Lewis acid (LA) catalysts in reducing the activation energies of polar Diels-Alder (P-DA) reactions have been studied within Molecular Electron Density Theory. To this end, a quantum topological energy partitioning scheme, namely, the Relative Interacting Atomic Energy (RIAE) analysis, is applied to the transition state structures (TSs) and the ground state of the reagents of two different LA-catalyzed P-DA reactions. Analyses of the ξEtotalX total energies of the two interacting frameworks f(X) show that the electronic energy stabilization of the electrophilic frameworks, resulting from the global electron density transfer (GEDT), is the cause of an effective decrease of the activation energies. On the other hand, an in-depth analysis of the ξEintraA intra-atomic energies of the atoms belonging to the electrophilic ethylenic framework in the LA-catalyzed P-DA reactions of cyclopentadiene with acrolein indicates that the strong electronic stabilization of the carbonyl carbon, resulting from the GEDT taking place at the TSs, is the main factor responsible for the decrease of the activation energies in these LA-catalyzed P-DA reactions. Finally, the increase in GEDT at the TSs of these P-DA reactions causes an increase in the larger C-C distance, resulting from the stabilization of the electrophilic framework, thereby decreasing the suggested Pauli repulsion.

A molecular electron density theory study of the bimolecular nucleophilic substitution reactions on monosubstituted methyl compounds.

The nucleophilic substitution reactions involving methyl monosubstituted compounds have been studied within the Molecular Electron Density Theory (MEDT) at the ωB97X-D/6-311+G(d,p) computational level in DMSO. This study aims to characterize the electronic nature of the transition state structures (TSs) involved in the so-called SN2 and SNi reactions. Both electron localization function and atom-in-molecules topological analyses indicate that the TSs involved in these nucleophilic substitutions can be described as a central methyl CH3+ carbocation, which is strongly stabilized by the presence of two neighbouring nucleophilic species through electron density transfer. This MEDT study establishes a significant electronic similarity between the so-called SN1 and SN2 reactions. Due to the weak electrophilic character of the methyl tetrahedral carbons, the departure of the leaving group should be expected with the approach of the nucleophile. However, while along the SN1 reactions, the strong stabilization of the tertiary carbocation does not demand the participation of the nucleophile, along the SN2 and SNi reactions involving primary tetrahedral carbons, the nucleophiles should participate in the reaction to stabilize the unstable methyl carbocation.

Exploring patients and caregivers needs and experiences in oncological physiotherapy: a call for collaborative care.

PURPOSE: This study explores whether the full potential of physiotherapy is reaching cancer patients and their caregivers at all stages of the oncological process, aiming to identify gaps and opportunities for improving care. METHODS: The World Cafe co-design methodology facilitated discussions among cancer patients and caregivers. This dynamic, inclusive, and engaging approach fostered diverse perspectives and deeper insights through collaborative and flexible discussions. Sessions were recorded, transcribed, and qualitatively analyzed. RESULTS: Sixteen participants were involved (eight cancer survivors and eight caregivers). The mean age of cancer survivors was 63.8 years, while the average age of caregivers was 59.3 years. Breast cancer was the most prevalent diagnosis among patients, and most caregivers had lost their family members to cancer. Analysis revealed two primary themes: "feeling cared for" and "the role of physiotherapy in the oncological process." Key findings highlight the need for more humanized healthcare, with professionals providing support through effective communication and empathy. Significant gaps were detected in both systematic referrals to physiotherapists and their integration into care teams. Testimonies highlighted the lack of knowledge about the full potential of physiotherapy in oncology, hindering access. There was also a demand for recognizing specialized oncological physiotherapists. CONCLUSIONS: These findings highlight significant gaps in physiotherapy care for cancer survivors and caregivers, including unmet needs due to the lack of information, resources, and effective communication. Future efforts should focus on increasing the visibility of physiotherapy, integrating specialized physiotherapists into oncology teams, and enhancing the emotional education of healthcare professionals to provide more humanized care.

Efficacy of different 8 h time-restricted eating schedules on visceral adipose tissue and cardiometabolic health: A study protocol.

BACKGROUND AND AIMS: To investigate the efficacy and feasibility of three different 8 h time-restricted eating (TRE) schedules (i.e., early, late, and self-selected) compared to each other and to a usual-care (UC) intervention on visceral adipose tissue (VAT) and cardiometabolic health in men and women. METHODS AND RESULTS: Anticipated 208 adults (50% women) aged 30-60 years, with overweight/obesity (25 ≤ BMI<40 kg/m2) and with mild metabolic impairments will be recruited for this parallel-group, multicenter randomized controlled trial. Participants will be randomly allocated (1:1:1:1) to one of four groups for 12 weeks: UC, early TRE, late TRE or self-selected TRE. The UC group will maintain their habitual eating window and receive, as well as the TRE groups, healthy lifestyle education for weight management. The early TRE group will start eating not later than 10:00, and the late TRE group not before 13:00. The self-selected TRE group will select an 8 h eating window before the intervention and maintain it over the intervention. The primary outcome is changes in VAT, whereas secondary outcomes include body composition and cardiometabolic risk factors. CONCLUSION: This study will determine whether the timing of the eating window during TRE impacts its efficacy on VAT, body composition and cardiometabolic risk factors and provide insights about its feasibility.

Unravelling the role of secretory Immnuoglobulin-A in COVID-19: a multicentre study in nursing homes during the first wave.

BACKGROUND: The function of mucosal secretory IgA (SIgA) seems to be paramount in the immune response against SARS-CoV-2 however, there are few studies addressing this issue specifically in the institutionalized older population. This study aims to determine the levels of secretory IgA against the S1 domain of the SARS-CoV-2 spike (SIgA-S1) in older people living in nursing homes (NH) and to investigate the differences in baseline characteristics, severity of COVID-19, duration of symptoms, 30-day mortality, and reinfection according to the levels of SIgA-S1. METHODS: In this multicentre longitudinal study, conducted in two NHs attended in coordination with a hospital-based Geriatric team, 305 residents (87.3 years, 74.4% female) were included. A massive collection of nasopharyngeal samples was carried out after the first wave of COVID-19 in May 2020 and an ELISA analysis of SIgA-S1 was performed on frozen samples in May 2023. Values of SIgA-S1 ≥ 57.6 U/mL ("cut-off point") were considered "induced". Resident medical records were reviewed to assess symptoms, comprehensive geriatric assessment (CGA), reinfection, and overall 30-day mortality. RESULTS: At the time of sample collection, 274 residents (89.8%) exhibited "induced" SIgA-S1 levels (≥ 57.6 U/mL), 46 (15.1%) tested positive for PCR SARS-CoV-2, and 170 (57%) had experienced COVID-19 symptoms. "Induced" SIgA-S1 patients were more likely to be symptomatic (60.3% vs. 29%; p < 0.001) and exhibited upper respiratory tract symptoms more frequently (25.1% vs. 6.5%; p = 0.020) compared to "non-induced" patients. Patients with severe disease and duration of symptoms > 10 days had higher levels of SIgA-S1 than those with mild disease (252 vs.192.6 U/mL; p = 0.012) or duration ≤ 10 days (270.5 vs. 208.1 U/mL; p = 0.043), respectively. No significant differences were observed in age, sex, CGA, duration of symptoms, disease severity, overall 30-day-mortality, or reinfection between "induced" and "non-induced" residents. CONCLUSIONS: Levels of SIgA-S1 are associated with the duration and type of COVID-19 symptoms, along with the severity of infection. While these findings shed light on the knowledge of SIgA-S1, further interdisciplinary studies are warranted to better understand the immune response to SARS-CoV-2 infection.

Assessing the Quality of Solvent-Assisted Lipid Bilayers Formed at Different Phases and Aqueous Buffer Media: A QCM-D Study.

Supported lipid bilayers (SLBs) are low-complexity biomimetic membranes, serving as popular experimental platforms to study membrane organization and lipid transfer, membrane uptake of nanoparticles and biomolecules, and many other processes. Quartz crystal microbalance with dissipation monitoring has been utilized to probe the influence of several parameters on the quality of SLBs formed on Au- and SiO2-coated sensors. The influence of the aqueous medium (i.e., buffer type) and the adsorption temperature, above and below the lipid melting point, is neatly explored for SLBs of 1,2-dimyristoyl-sn-glycero-3-phosphocholine and 1,2-dipalmitoyl-sn-glycero-3-phosphocholine formed by a solvent exchange. Below the lipid melting temperature, quality variations are observed upon the formation on Au and SiO2 surfaces, with the SLBs being more homogeneous for the latter. We further investigate how the buffer affects the detection of lipid melting in SLBs, a transition that necessitates high-sensitivity and time-consuming surface-sensitive techniques to be detected.

Smartphone Ownership, Minors' Well-being, and Parental Mediation Strategies. An Analysis in the Context of Social Media Influencers.

Although smartphone ownership among minors has become an important social phenomenon, its impact on children's and adolescents' well-being, as well as the mechanisms by which this might take place are not yet sufficiently well-established. To date, no research has examined the effect of smartphone ownership on the well-being of minors through the consumption of influencer-generated content, nor has it explored the effectiveness of the main prevention strategies employed by parents in this context. To fill those gaps, 800 Spanish minors (50% female) aged from 8 to 16 years old (M = 12.33, SD = 2.38) participated in a correlational study in which the ownership of electronic devices, the consumption of influencer generated content, the parasocial relationship with the influencer, and the most common parental mediation strategies were considered. The results showed a positive association between electronic device ownership and psychological discomfort, problematic usage, and imitation of dangerous behaviors. This association was mediated by the consumption of influencer-generated content and the parasocial relationship established by the minor with the influencer. Regarding preventive strategies, only active mediation was inversely related to poorer well-being indicators, however this positive effect significantly decreased when a smartphone or a similar electronic device was owned by the minor (vs. no owned). These findings contribute to the understanding of how smartphone ownership can affect the well-being of children, emphasizing the need for thoughtful consideration when deciding whether to provide smartphones to minors.

Lateral kangaroo position for thermal stability of extremely preterm: Non-inferiority randomized controlled trial.

BACKGROUND: Kangaroo care (KC) is an evidence-based best practice that can prevent major health complications in preterm infants. However, there is a lack of evidence on the feasibility and safety of placing extremely preterm infants under 28 weeks gestational age in KC position. AIM: To compare thermal stability 60 min after the first KC session in the lateral versus prone position in extremely preterm infants under 28 weeks gestational age. STUDY DESIGN: This is a single-centre, randomized, non-inferiority, parallel clinical trial. The patients were extremely preterm infants during their first 5 days of life. Infants in the intervention group received KC in the lateral position while those in the control group received KC in the prone position. All infants receiving KC were inside their polyethylene bags but maintained skin-to-skin contact. The primary outcome was the axillary temperature of the infants, and the secondary outcome was the development of intraventricular haemorrhage. RESULTS: Seventy infants were randomized (35 per group). The mean gestational age was 26 +1(1+1) in both groups. In the first KC session, the infant temperature at 60 minutes was 36.79°C (0.43) in lateral KC position, and 36.78°C (0.38) in prone KC position (p = .022). In lateral KC position, 7.69% (2) of the children who, according to the cranial ultrasound performed before the first session, had no haemorrhage presented with intraventricular haemorrhage after the first session. In prone KC position, new haemorrhages appeared after the first session in 29.17% (7) (p = .08). CONCLUSIONS: The lateral KC position is an alternative to the conventional prone KC position and maintains normothermia in infants under 28 weeks gestational age. RELEVANCE TO CLINICAL PRACTICE: Extremely preterm infants are candidates for KC. Lateral KC position is an evidence-based best practice that can be applied to preterm infants under 28 weeks GA. This evidence is particularly useful in performing umbilical catheterization on these patients.

[Systematic review of the primary care quality assessment instruments used in the last 10 years]. / Revisión sistemática de los instrumentos de evaluación de la calidad de Atención Primaria utilizados en los últimos 10 años.

OBJECTIVE: There are numerous instruments in the scientific literature for the evaluation of the quality of Primary Care (PC) and to know which of them are the most used and in which countries provides more information to make a well-founded decision. The aim is to determine which, between 2013 and 2023, have been the instruments used to assess the international quality of PC, its evolution and geographical distribution. DESIGN: Systematic review. DATA SOURCES: PubMed and Embase. From March to December 2023. INCLUSION CRITERIA: 1) Validation studies of specific assessment instruments to measure the quality of PC and/or the satisfaction of patients, providers or managers. 2) carried out in the field of PC and 3) published between 1/01/2013 and 01/02/2023. 83 full-text articles were included. DATA EXTRACTION: From each publication, an instrument used to evaluate the quality of the PC, attributes of the PC it evaluates, recipient of the evaluation, user, provider or manager, year, and country. RESULTS: Fifteen PC assessment instruments were found. The most widely used is the Primary Care Assessing Tool (PCAT), with wide geographical distribution, versions in several languages, is more limited in Europe, except in Spain, and is mostly used in the Primary Care Assessing Tool (PCAT). CONCLUSIONS: The PCAT, due to its cultural adaptability, availability in several languages, its ability to evaluate the fundamental principles of PC enunciated by the World Health Organization and to contemplate the perspectives of all health agents, is a complete, versatile, and consistent questionnaire for the evaluation of the quality of PC.

Magnesium homeostasis in deoxygenated sickle erythrocytes is modulated by endothelin-1 via Na+ /Mg2+ exchange.

Painful crises in sickle cell disease (SCD) are associated with increased plasma cytokines levels, including endothelin-1 (ET-1). Reduced red cell magnesium content, mediated in part by increased Na+ /Mg2+ exchanger (NME) activity, contributes to erythrocyte K+ loss, dehydration and sickling in SCD. However, the relationship between ET-1 and the NME in SCD has remained unexamined. We observed increased NME activity in sickle red cells incubated in the presence of 500 nM ET-1. Deoxygenation of sickle red cells, in contrast, led to decreased red cell NME activity and cellular dehydration that was reversed by the NME inhibitor, imipramine. Increased NME activity in sickle red cells was significantly blocked by pre-incubation with 100 nM BQ788, a selective blocker of ET-1 type B receptors. These results suggest an important role for ET-1 and for cellular magnesium homeostasis in SCD. Consistent with these results, we observed increased NME activity in sickle red cells of three mouse models of sickle cell disease greater than that in red cells of C57BL/J6 mice. In vivo treatment of BERK sickle transgenic mice with ET-1 receptor antagonists reduced red cell NME activity. Our results suggest that ET-1 receptor blockade may be a promising therapeutic approach to control erythrocyte volume and magnesium homeostasis in SCD and may thus attenuate or retard the associated chronic inflammatory and vascular complications of SCD.

IgG antispike persistence and immunophenotype in children infected by SARS-CoV-2.

AIM: The immune status of children recovering from SARS-CoV-2 infection is not completely understood. We describe IgG antispike persistence in children infected during the first two pandemic waves. In addition, we compared with healthy controls their leukocyte populations and CD64 expression. METHODS: Cross-sectional study. Carried out from October 2021 to February 2022 in nonreinfected and nonvaccinated children with SARS-CoV-2 in 2020. The presence of antispike IgG was studied using chemiluminescent immunoassay. Leukocyte populations were analysed using flow cytometry and marked for CD45, CD4, CD8 and CD64. Statistical minor than 0.05 was considered significant. RESULTS: One hundred and eighty-three control and 77 patients were included. IgG antispike determinations were performed after a median of 501 days (262-464); 52 of 77 children were positive. Cases showed significantly higher percentages of monocytes, lymphocytes, CD8+ and CD4+ . In addition, CD64 expression was higher in monocytes and neutrophils. The presence of IgG antispike was accompanied by a higher percentage of CD64+ neutrophils. CONCLUSION: In our series, the SARS-CoV-2 IgG antispike protein was usually positive beyond 1 year after infection. Furthermore, leukocyte populations from cases differ from controls, with higher CD64 expression on neutrophils and monocytes. Prospective clinical observations are required to confirm the implications of these findings.

Effectiveness of Water-Based Exercise in Patients with Chronic Obstructive Pulmonary Disease: Systematic Review and Meta-Analysis.

Chronic obstructive pulmonary disease (COPD) is a progressive respiratory disease that, due to dyspnea, decreases patients' physical function and quality of life. The aim of the research was to evaluate the effectiveness of water-based exercise (WE) in improving functional capacity and respiratory muscle strength in patients with COPD. It consisted of a systematic review and meta-analysis of eight randomized clinical trials (RCTs) from the last 10 years, found in PubMed, PEDro, Scopus and Web of Science databases. Methodological quality was analyzed using the PEDro scale and the Cochrane Collaboration Risk of Bias Tool. Regarding the evaluation of functional capacity, mainly assessed were lung function, respiratory muscle strength, and maximal or aerobic exercise. The results showed that WE improves functional capacity compared to a non-exercising control group (SMD: 73.42; IC 95%: 40.40 to 106.45; I2: 0%). There are no statistically significant differences between a WE treatment and a land exercise (LE) treatment (p = 0.24) in functional capacity, nor with respect to respiratory muscle strength (p = 0.97). These data should be interpreted with caution, as more RCTs with aquatic intervention in COPD patients are needed to elucidate whether there are differences between WE or LE according to patient characteristics and comorbidities.

Efficacy of Specific Trunk Exercises in the Balance Dysfunction of Patients with Parkinson's Disease: A Systematic Review and Meta-Analysis.

Parkinson's disease (PD) is a neurodegenerative pathology classified as a movement disorder. Physical exercise within a physiotherapy program is an important element to improve postural stability, balance and mobility in order to reduce falls in people with PD. The aim of this work was to determine the efficacy of specific balance and trunk mobility exercises, as well as their benefits for and effects on patients with idiopathic PD. A systematic review and meta-analysis was conducted according to PRISMA standards. The search was performed in five databases: Cochrane Library, SciELO, PEDro, Scopus and PubMed, in February 2022 with the following descriptors: Parkinson's disease, trunk, exercise, therapy and physical therapy. The inclusion criteria were randomized controlled trials (RCTs) over the last ten years. A meta-analysis on static and dynamic balance was conducted with the software Review Manager. Nine articles met the objectives and inclusion criteria, with a total of 240 participants. The trials had moderate methodological quality according to the PEDro scale. The studies included differed with regard to intervention protocol and outcome measures. Finally, eight studies were included in a quantitative analysis in which it was shown that trunk-specific exercises interventions did not significantly improve static balance (SMD = -0.10, 95% CI = -0.29, 0.08; p = 0.28) or dynamic balance (SMD = 0.64 95% CI = -0.24, 1.52; p = 0.15). However, significant differences were found in static balance measured subjectively using the Berg Balance Scale (SMD = -0.52, 95% CI = -1.01, -0.02; p = 0.04). Although some differences were not significant, the studies included in this systematic review consider that specific trunk exercises or balance training combined with muscle strengthening in patients with idiopathic PD should be a complement to pharmacological treatment for improving balance dysfunction and postural instability, preventing falls and promoting wellness.

GIST is not all that it seems.

We present a 41-year-old female who was admitted to our hospital with a history of 2-month epigastric pain and vomiting. Physical examination was normal. Upper gastrointestinal endoscopy showed a sessile submucosal tumor with central ulceration in the gastric body-antrum. Biopsies revealed a gastric mucosa without changes. Nevertheless, endoscopic ultrasound-guided biopsies showed interlacing bundles of spindle cells. The immunohistochemical study was negative for CD117 and smooth muscle actin and positive for S100 protein. A CT scan identified a heterogeneous mass in the stomach wall.

The effects of biological sex and cardiovascular disease on COVID-19 mortality.

Cardiovascular disease (CVD) is a common comorbidity observed in patients with coronavirus disease 2019 (COVID-19), which is associated with increased severity and mortality. However, the effects of biological sex on CVD-associated mortality in patients with COVID-19 are poorly established, particularly among Hispanic/Latin Americans. We examined the association of preexisting CVD with COVID-19 mortality in hospitalized Latin American men and women. This multicenter study included Mexican patients hospitalized with a positive diagnosis of COVID-19. The main outcome was in-hospital mortality. Multivariable regression analyses were used to calculate the adjusted odds ratio with 95% confidence interval for mortality in women and men. Of 81,400 patients with a positive diagnosis for SARS-CoV-2 infection, 28,929 (35.54%) hospitalized patients were evaluated. Of these, 35.41% (10,243) were women. In-hospital death was higher in men than in women. In relation to CVD between the sexes, women had a higher incidence of CVD than men (4.69 vs. 3.93%, P = 0.0023). The adjusted logistic regression analyses showed that CVD was significantly associated with COVID-19 mortality in women but not men. We then stratified by sex according to age <52 and ≥52 yr old. Similar significant association was also found in prespecified analysis in women ≥52 yr old but not in men of similar age. We conclude that CVD's effect on mortality among patients hospitalized with COVID-19 is dependent on biological sex and age in this Latin American cohort. These results suggest that therapeutic strategies for Latin American women with CVD and COVID-19 should include particular attention to their cardiovascular health.NEW & NOTEWORTHY CVD's effect on COVID-19 mortality is dependent on biological sex and age. CVD in women but not men with COVID-19 is associated with significantly unfavorable outcomes.

COVID-19 vaccine candidates based on modified vaccinia virus Ankara expressing the SARS-CoV-2 spike induce robust T- and B-cell immune responses and full efficacy in mice.

Vaccines against SARS-CoV-2, the causative agent of the COVID-19 pandemic, are urgently needed. We developed two COVID-19 vaccines based on modified vaccinia virus Ankara (MVA) vectors expressing the entire SARS-CoV-2 spike (S) protein (MVA-CoV2-S); their immunogenicity was evaluated in mice using DNA/MVA or MVA/MVA prime/boost immunizations. Both vaccines induced robust, broad and polyfunctional S-specific CD4+ (mainly Th1) and CD8+ T-cell responses, with a T effector memory phenotype. DNA/MVA immunizations elicited higher T-cell responses. All vaccine regimens triggered high titers of IgG antibodies specific for the S, as well as for the receptor-binding domain; the predominance of the IgG2c isotype was indicative of Th1 immunity. Notably, serum samples from vaccinated mice neutralized SARS-CoV-2 in cell cultures, and those from MVA/MVA immunizations showed a higher neutralizing capacity. Remarkably, one or two doses of MVA-CoV2-S protect humanized K18-hACE2 mice from a lethal dose of SARS-CoV-2. In addition, two doses of MVA-CoV2-S confer full inhibition of virus replication in the lungs. These results demonstrate the robust immunogenicity and full efficacy of MVA-based COVID-19 vaccines in animal models and support its translation to the clinic.IMPORTANCE The continuous dissemination of the novel emerging SARS-CoV-2 virus, with more than 78 million infected cases worldwide and higher than 1,700,000 deaths as of December 23, 2020, highlights the urgent need for the development of novel vaccines against COVID-19. With this aim, we have developed novel vaccine candidates based on the poxvirus modified vaccinia virus Ankara (MVA) strain expressing the full-length SARS-CoV-2 spike (S) protein, and we have evaluated their immunogenicity in mice using DNA/MVA or MVA/MVA prime/boost immunization protocols. The results showed the induction of a potent S-specific T-cell response and high titers of neutralizing antibodies. Remarkably, humanized K18-hACE2 mice immunized with one or two doses of the MVA-based vaccine were 100% protected from SARS-CoV-2 lethality. Moreover, two doses of the vaccine prevented virus replication in lungs. Our findings prove the robust immunogenicity and efficacy of MVA-based COVID-19 vaccines in animal models and support its translation to the clinic.

On the Notation of Catastrophes in the Framework of Bonding Evolution Theory: Case of Normal and Inverse Electron Demand Diels-Alder Reactions.

This paper generalizes very recent and unexpected findings [J. Phys. Chem. A, 2021, 125, 5152-5165] regarding the known "direct- and inverse-electron demand" Diels-Alder mechanisms. Application of bonding evolution theory indicates that the key electron rearrangement associated with significant chemical events (e. g., the breaking/forming processes of bonds) can be characterized via the simplest fold polynomial. For the CC bond formation, neither substituent position nor the type of electronic demand induces a measurable cusp-type signature. As opposed to the case of [4+2] cycloaddition between 1,3-butadiene and ethylene, where the two new CC single bonds occur beyond the transition state (TS) in the activated cases, the first CC bond occurs in the domain of structural stability featuring the TS, whereas the second one remains located in the deactivation path connecting the TS with the cycloadduct.

Nanomechanical Stability of Laterally Heterogeneous Films of Corrosion Inhibitor Molecules Obtained by Microcontact Printing on Au Model Substrates.

Self-assembled monolayers of corrosion inhibitors of the mercaptobenzimidazole family, SH-BimH, SH-BimH-5NH2, and SH-BimH-5OMe, were formed on template-stripped ultraflat Au surfaces using microcontact printing, and subsequently analyzed using X-ray photoelectron spectroscopy (XPS), atomic force microscopy (AFM), and AFM-force spectroscopy (AFM-FS) using a quantitative imaging (QI) mode. Printing of all used inhibitor molecules resulted in clear patterns and in slightly more compact films compared to immersion. The stability of the monolayers is further probed by AFM-FS. Adhesion values of laterally heterogeneous inhibitor-modified surfaces compared to bare Au surfaces, nonpatterned areas, and fully covered surfaces are analyzed and discussed. Microcontact printing confers a superior nanomechanical stability to imidazole-modified films of the printed surface patches as compared to homogeneously covered surfaces by immersion into the inhibitor solution.